Building C(sp(3))-rich Complexity by Combining Cycloaddition and C–C Cross Coupling Reactions

Prized for their ability to rapidly generate complexity in building new ring systems and stereocenters(1), cycloadditions have featured in numerous total syntheses(2) and are a key component in the education of chemistry students(3). Similarly, C–C cross-coupling methods are integral to synthesis due to their programmability, modularity, and reliability(4). Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat, sp(2)-rich architectures(5). Despite the ability of cycloadditions to introduce multiple C(sp(3)) centres in a single step, they are less used(6). This is likely due to a striking lack of modularity stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here, we demonstrate a strategy for taking the optimal features of these two essential transforms and combining them into one simple sequence to enable the modular, enantioselective, scalable, and programmable preparation of useful building blocks, natural products, and lead scaffolds for drug discovery.